Evidence map›Paper›PMID 38720063›Full record

ArticleCellular & molecular immunology2024

Neutrophil-derived PAD4 induces citrullination of CKMT1 exacerbates mucosal inflammation in inflammatory bowel disease.

Shuling Wang, Yihang Song, Zhijie Wang, Xin Chang, Haicong Wu, Ziwei Yan, Jiayi Wu, Zixuan He, Le Kang, Wenjun Hu and 4 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cellular & molecular immunology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
38citing papers in PubMed, 1 pooled it
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

38 citing papers in PubMed, 1 synthesis or guideline pooled it.

  1. Pooled it
  2. Article
  3. MMP8 Promotes NETosis in Gestational Diabetes Mellitus.Antioxidants (Basel, Switzerland) · 2026
    Article
  4. Article
  5. Article
  6. Article
  7. Review
  8. Article
  9. Review
  10. Gut · 2026
    Article
  11. Article
  12. Review
  13. Review
  14. Article
  15. Article
  16. Review
  17. Review
  18. Review
  19. Review
  20. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

14 authors.

Shuling Wang *National Clinical Research Center for Digestive Diseases, Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai, 200433, China.
Yihang Song *National Clinical Research Center for Digestive Diseases, Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai, 200433, China.
Zhijie Wang *National Clinical Research Center for Digestive Diseases, Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai, 200433, China.ORCID 0000-0001-8015-5413
Xin Chang *National Clinical Research Center for Digestive Diseases, Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai, 200433, China.
Haicong Wu *National Clinical Research Center for Digestive Diseases, Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai, 200433, China.
Ziwei Yan *National Key Laboratory of Immunology and Inflammation, Naval Medical University, Shanghai, 200433, China.
Jiayi WuNational Key Laboratory of Immunology and Inflammation, Naval Medical University, Shanghai, 200433, China.
Zixuan HeChanghai Clinical Research Unit, Changhai Hospital, Naval Medical University, Shanghai, 200433, China.
Le KangDepartment of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai, 200433, China.
Wenjun HuNational Key Laboratory of Immunology and Inflammation, Naval Medical University, Shanghai, 200433, China.
Tian XiaNational Clinical Research Center for Digestive Diseases, Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai, 200433, China.
Zhaoshen LiNational Clinical Research Center for Digestive Diseases, Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai, 200433, China. li.zhaoshen@hotmail.com.ORCID 0000-0003-0404-242X
Xingxing RenInstitute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China. renxxing@ustc.edu.cn.ORCID 0000-0002-8601-5216
Yu BaiNational Clinical Research Center for Digestive Diseases, Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai, 200433, China. baiyu1998@hotmail.com.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Peptidyl arginine deiminase 4 (PAD4) plays a pivotal role in infection and inflammatory diseases by facilitating the formation of neutrophil extracellular traps (NETs). However, the substrates of PAD4 and its exact role in inflammatory bowel disease (IBD) remain unclear. In this study, we employed single-cell RNA sequencing (scRNA-seq) and substrate citrullination mapping to decipher the role of PAD4 in intestinal inflammation associated with IBD. Our results demonstrated that PAD4 deficiency alleviated colonic inflammation and restored intestinal barrier function in a dextran sulfate sodium (DSS)-induced colitis mouse model. scRNA-seq analysis revealed significant alterations in intestinal cell populations, with reduced neutrophil numbers and changes in epithelial subsets upon PAD4 deletion. Gene expression analysis highlighted pathways related to inflammation and epithelial cell function. Furthermore, we found that neutrophil-derived extracellular vesicles (EVs) carrying PAD4 were secreted into intestinal epithelial cells (IECs). Within IECs, PAD4 citrullinates mitochondrial creatine kinase 1 (CKMT1) at the R242 site, leading to reduced CKMT1 protein stability via the autophagy pathway. This action compromises mitochondrial homeostasis, impairs intestinal barrier integrity, and induces IECs apoptosis. IEC-specific depletion of CKMT1 exacerbated intestinal inflammation and apoptosis in mice with colitis. Clinical analysis of IBD patients revealed elevated levels of PAD4, increased CKMT1 citrullination, and decreased CKMT1 expression. In summary, our findings highlight the crucial role of PAD4 in IBD, where it modulates IECs plasticity via CKMT1 citrullination, suggesting that PAD4 may be a potential therapeutic target for IBD.

Indexed as

CitrullinationInflammationInflammatory Bowel DiseasesIntestinal MucosaMice, Inbred C57BLNeutrophilsProtein-Arginine Deiminase Type 4AnimalsColitisCreatine KinaseDextran SulfateDisease Models, AnimalHumansMaleMiceMice, KnockoutCreatine KinaseDextran SulfatePADI4 protein, humanpeptidylarginine deiminase 4, mouseProtein-Arginine Deiminase Type 4CitrullinationInflammatory bowel diseaseIntestinal epithelial cellsMitochondrial creatine kinase 1Peptidyl-arginine deiminase-4

Identifiers

PMID38720063
PMCPMC11143373

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.